Nuclear physicists turn to drug development

Can techniques developed to solve physics problems help develop new drugs?

Some of the hardest problems in physics are phase transitions, such as freezing water or cooling a metal until it can superconduct. When a physical system goes through a phase transition its fundamental properties change. Even if we understand the material in either state, the behavior right near the phase transition can be very complex and difficult to understand. In developing our understanding of what happens during phase transitions physicists have developed some sophisticated mathematical tricks to help them. So how does this help with drug development?

Many drugs target, either through design or accident, a protein or enzyme and act by blocking the active site that does the actual work. This is a time consuming and frustrating process, which is made more difficult by often not knowing the exact shape of the active region. One approach to this, which team egg roll is doing its bit for, is to take a protein sequence and fold it up as many ways as possible and find the shape that has the highest stability. Unfortunately, this approach is like looking for a needle in a haystack because any sequence can fold up many ways but only one fold is the stable. A second approach takes the inverse of this problem and starts out with a likely shape and then figures out the correct sequence, since there are fewer sequences that can fold to the appropriate shape it doesn't take as long to find a sequence shape match. All of these are vital to understanding mechanisms and roles in cell processes.

Now a group of Italian physicists, in collaboration with various biologically knowledgeable people have come up with an alternative approach. They have found that folding can behave like a particular set of phase transitions, where the folding will not occur if a particular part of the sequence is interfered with. Thus, a new class of drugs presents itself. The drug is now a compound which is designed to bind to this critical part of the sequence that prevents the protein from folding. Since the protein is not folded there is no active region and the protein cannot do its job. Another advantage is that there is no single critical sequence, and every critical sequence is repeated several times, thus a potential drug is relatively immune to mutation. The researchers involved think that this class of drugs may well be effective against various fast mutating virus, such as HIV and influenza.

I have to say that this is a fantastic piece of work. This is an entirely new approach to drug development, which could target multiple proteins in the same pathogen. It could also speed up the discovery stage of drug development, since once the sequence is determined the drug is then designed. Finally, the chemical that prevents the folding is itself a modified protein so it is unlikely to be toxic and produce side effects. At present they are concentrating on the development of a influenza vaccine.

Chris Lee / Chris writes for Ars Technica's science section. A physicist by day and science writer by night, he specializes in quantum physics and optics. He lives and works in Eindhoven, the Netherlands.